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Hypothermia therapy for neonatal encephalopathy
= The History of Hypothermic Neural Rescue for Birth Asphyxia = Hypothemia for resuscitation Many physicians over the centuries have tried to resuscitate babies after birth by altering their temperatures, essentially aiming to animate the infant by inducing the onset of breathing see: Wang H, Olivero W, Wang D Lanzino G. Cold as a therapeutic agent Acta Neurochir (Wien) (2006) 148: 565–570 . Little thought was given to brain protection, because cerebral hypoxia during birth was not linked with later neurological problems until William John Little in 1861 Little WJ. On the influence of abnormal parturition, difficult labours, premature birth, and asphyxia neonatorum, on the mental and physical condition of the child, especially in relation to deformities. see:Clin.Orthop.Relat Res. 1966;46:7-22. , and even then this was controversial; Sigmund Freud, for example, famously disagreed, and when scientific studies of neonatal therapeutic hypothermia were begun in the 1950's researchers like Bjorn Westin still reported their work in terms of re-animation rather than neuroprotection Westin B. Hypothermia in the resuscitation of the neonate: a glance in my rear-view mirror. Acta Paediatr. 2006;95:1172-4. . Investigators such as James Miller and Clement Smith carried out clinical observations and careful physiological experimentsMiller JA. Factors in Neonatal Resistance to Anoxia. I. Temperature and Survival of Newborn Guinea Pigs Under Anoxia. Science 1949;110:113-4. Enhorning G,.Westin B. Experimental studies of the human fetus in prolonged asphyxia. Acta Physiol Scand. 1954;31:359-75. Westin B, Miller JA, Nyberg R, Wedenberg E. Neonatal asphyxia pallida treated with hypothermia alone or with hypothermia and transfusion of oxygenated blood. Surgery 1959;45:868-79. Auld PA, Nelson NM, Nicopopoulos DA, Helwig F, Smith CA. Physiologic studies on an infant in deep hypothermia. N.Engl.J.Med. 1962;267:1348-51. , but although some babies were conscientiously followed up, they were not mainly concerned with long term neurological outcome. However, by the 1960's physicians saw hypothermia after delivery was something to be avoided. The problem of infants who failed to breath at birth had been solved by the invention of mechanical ventilation, so any benefit cooling might have for re-animation was no longer needed, and an influential trial showed that keeping small and preterm infants warm increased survival Silverman WS, Fertig JW, Berger AP. The influence of the thermal environment upon the survival of newly born permature infants. Pediatrics 1958;876-85. . These results, together with observational Mann TP,.Elliott RIK. Neonatal cold injury due to accidental exposure to cold. Lancet 1957;229-34. and experimental Brodie HR, Cross KW, Lomer TR. Heat production in new-born infants under normal and hypoxic conditions. J.Physiol 1957;138:156-63. data made it an article of medical faith for decades that babies should not be allowed to get cold. Consequently during the next two decades studies of neonatal hypothermia in Europe and the USA were sporadic and often unsuccessful. An interest in cooling for brain protection was beginning to emerge, but contemporary neuroscience provided few useful concepts to guide this research and little progress was made. Miller JA, Jr., Zakary R, Miller FS. Hypothermia, Asphyxia, and cardiac glycogen in guinea pigs. Science 1964;144:1226-7. Dunn JM,.Miller JA, Jr. Hypothermia combined with positive pressure ventilation in resuscitation of the asphyxiated neonate. Clinical observations in 28 infants. Am.J.Obstet.Gynecol. 1969;104:58-67 Ehrstrom J, Hirvensalo M, Donner M, Hietalahti J. Hypothermia in the resuscitation of severely asphyctic newborn infants. A follow-up study. Ann.Clin.Res. 1969;1:40-9. Cordey R, Chiolero R, Miller JA, Jr. Resuscitation of neonates by hypothermia: report on 20 cases with acid-base determination on 10 cases and the long-term development of 33 cases. Resuscitation. 1973;2:169-81. Oates RK,.Harvey D. Failure of hypothermia as treatment for asphyxiated newborn rabbits. Arch.Dis.Child 1976;51:512-6. Michenfelder JD,.Milde JH. Failure of prolonged hypocapnia, hypothermia, or hypertension to favorably alter acute stroke in primates. Stroke 1977;8:87-91. Bohn DJ, Biggar WD, Smith CR, Conn AW, Barker GA. Influence of hypothermia, barbiturate therapy, and intracranial pressure monitoring on morbidity and mortality after near-drowning. Crit Care Med. 1986;14:529-34. . Although across the Iron Curtain in the Soviet Union cooling was being applied empirically following birth asphyxia Kopshev SN. hypothermia in the prevention and combined therapy of cerebral pathology in infants with asphyxia neonatorum. Akush.Ginekol.(Mosk) 1982;56-8. , the language barrier, cold war politics and the Russians’ failure to carry out randomised controlled trials contributed to an almost total ignorance of this work in the West. Indeed a group of Russian neonatologists who described hypothermic neural rescue during a visit to the Neonatal Unit in Bristol, UK, met with little interest Prof Peter Dunn, Bristol, personal communication Neural Rescue In the late 1980‘s the development of a new set of concepts and problems led to a re-examination. A new generation of neonatal researchers were influenced by the growing evidence that protecting the brain against the effects of oxygen deprivation during labour might be possible. These researchers were aware that cooling produced powerful intra-ischaemic neuroprotection during cardiac surgery but a new concept of hypothermic post-insult neural rescue developed. This shift in thinking was possible because of at least three major new ideas that were developing at the same time: delayed post-ischaemic cell death; excitotoxicity; and apoptosis. Delayed Cell Death The first paradigm shift that affected neonatal researchers in particular was the idea that if a baby was resuscitated after cerebral hypoxia-ischaemia there was a period of time before brain cells started to die. Osmund Reynolds at University College London used the newly developed technique of Magnetic Resonance Spectroscopy (MRS) to show that the infant brain metabolism is normal in the hours after birth asphyxia and deteriorated only after a distinct delay Delpy DT, Gordon RE, Hope PL, Parker D, Reynolds EO, Shaw D et al. Noninvasive investigation of cerebral ischemia by phosphorus nuclear magnetic resonance. Pediatrics 1982;70:310-3. . Robert Vannucci confirmed the effect with painstaking biochemistry Vannucci RC. Experimental biology of cerebral hypoxia-ischemia: Relation to perinatal brain damage. Pediatr.Res. 1990;27:317-26. , and delayed injury was also reported in neuropathological studies Kirino T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res. 1982;239:57-69. Pulsinelli WA, Brierley JB, Plum F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann.Neurol. 1982;11:491-8. . Delayed brain injury (called ‘secondary energy failure’ by Reynolds) was a critical new idea. If brain cells remained normal for a time and the mechanism of the delayed death could be unravelled, it opened the possibility of therapeutic intervention in what had previously seemed an impossible situation Hope PL, Costello AM, Cady EB, Delpy DT, Tofts PS, Chu A et al. Cerebral energy metabolism studied with phosphorus NMR spectroscopy in normal and birth-asphyxiated infants. Lancet 1984;2:366-70. . Excitotoxicity The new and transforming concept of excitotoxicity developed from the seminal experiments of John Olney Olney JW,.Sharpe LG. Brain lesions in an infant rhesus monkey treated with monsodium glutamate. Science 1969;166:386-8. Olney JW,.Ho OL. Brain damage in infant mice following oral intake of glutamate, aspartate or cysteine. Nature 1970;227:609-11. and Brian Meldrum Simon RP, Swan JH, Griffiths T, Meldrum BS. Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science 1984;226:850-2. . They showed that at least some of the neural cell death caused by hypoxia-ischaemia is mediated by excess production of the excitatory neurotransmitter glutamate, and that pharmacological blockade of the N-methyl-D-aspartate receptor could provide good protection against hypoxic damage. Olney and Meldrum had shifted the paradigm, allowing researchers to think of hypoxic-ischaemic damage as a treatable disease. Apoptosis However, it was still a mystery how and why cells triggered by hypoxia-ischaemia should die hours or days later, particularly when it became clear that glutamate levels were not particularly high during secondary energy failure. The next critical idea came with the discovery of programmed cell death, a novel form of cell suicide. Originally observed as a pathological appearance and named apoptosis (“falling off", as of leaves) in the 1970’s Kerr JF, Wyllie AH, Currie AR. Apoptosis, a basic biological phenomenon with wide-ranging implications in human tissue kinetics. Br.J.Cancer 1972;26:239-57. , Horvitz Ellis HM,.Horvitz HR. Genetic control of programmed cell death in the nematode C. elegans. Cell 1986;44:817-29 , Raff Raff MC. Social controls on cell survival and cell death. Nature 1992;356:397-400. and Evan Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992;69:119-28. provided a molecular understanding and showed that apoptosis could be triggered by cellular insults. The radical idea that hypoxia-ischaemia triggered a cell suicide programme which could explain the perplexing phenomenon of delayed cell death was soon supported by experimental Mehmet H, Yue X, Squier MV, Lorek A, Cady E, Penrice J et al. Increased apoptosis in the cingulate sulcus of newborn piglets following transient hypoxia-ischaemia is related to the degree of high energy phosphate depletion during the insult. Neurosci.Lett. 1994;181:121-5. Beilharz E, Williams CE, Dragunow M, Sirimanne E, Gluckman PD. Mechanisms of cell death following hypoxic-ischaemic injury in the immature rat: evidence of apoptosis during selective neuronal loss. Mol.Brain.Res. 1995;29:1-14. and human data Edwards AD, Yue X, Cox P, Hope PL, Azzopardi D, Squier MV et al. Apoptosis in the brains of infants suffering intrauterine cerebral injury. Pediatr Res 1997;42:684-9. , and may researchers believe this helps explain why neural rescue works in the newborn. However the picture is complex: both apoptosis and necrosis are present in variable proportions Northington FJ, Graham EM, Martin LJ. poptosis in perinatal hypoxic-ischemic brain injury: how important is it and should it be inhibited?Brain Res Brain Res Rev. 2005 Dec 15;50(2):244-57. ; and there seems to be prolonged neurodegeneration after an insult Stone BS, Zhang J, Mack DW, Mori S, Martin LJ, Northington FJ. Delayed neural network degeneration after neonatal hypoxia-ischemia. Ann Neurol. 2008 Nov;64(5):535-46. Research into this problem continues. Neonatal Neural Rescue These ideas flowed through the perinatal research community, producing a new belief that neural rescue after birth asphyxia should be possible. Amongst the first to have attempt neonatal neural rescue in animals were Ingmar Kjellmer and Henrik Hagberg in Gothenburg Thiringer K, Hrbek A, Karlsson K, Rosen KG, Kjellmer I. Postasphyxial cerebral survival in newborn sheep after treatment with oxygen free radical scavengers and a calcium antagonist. Pediatr.Res. 1987;22:62-6. Hagberg H, Andersson P, Kjellmer I, Thiringer K, Thordstein M. Extracellular overflow of glutamate, aspartate, GABA and taurine in the cortex and basal ganglia of fetal lambs during hypoxia-ischemia. Neurosci.Lett. 1987;78:311-7. , and Michael Johnston in Baltimore McDonald JW, Silverstein FS, Johnston MV. MK-801 protects the neonatal brain from hypoxic-ischemic damage. Eur.J.Pharmacol. 1987;140:359-61. . The potential began to draw in other neonatal researchers from diverse fields to begin neuroprotection research, including those who came to form the informal neonatal hypothermia research group: Peter Gluckman and Tania Gunn were endocrinologists in the University of Auckland New Zealand and interested in cooling for its effect on thyroid function; they had first cooled a sheep fetus for endocrine studies in 1983. Denis Azzopardi, John Wyatt and David Edwards, then young researchers working for Reynolds, were using Reynolds’s sophisticated MRS approach to replicate secondary energy failure in newborn piglets Lorek A, Takei Y, Cady EB, Wyatt JS, Penrice J, Edwards AD et al. Delayed ('secondary') cerebral energy failure following acute hypoxia-ischaemia in the newborn piglet: continuous 48-hour studies by 31P magnetic resonance spectroscopy. Pediatr Res 1994;36:699-706. and immature rats Blumberg RM, Cady EB, Wigglesworth JS, McKenzie JE, Edwards AD. Relation between delayed impairment of cerebral energy metabolism and infarction following transient focal hypoxia ischaemia in the developing brain. Exp.Brain Research 1996;113:130-7. ; in Gluckman’s laboratory Alistair Gunn and Chris Williams developed a simple and elegant biophysical method using cerebral impedance to do essentially the same thing in fetal sheep Williams CE, Gunn AJ, Mallard C, Gluckman PD. Outcome after ischemia in the developing sheep brain: an electroencephalographic and histological study. Ann.Neurol. 1992;31:14-21. . Marianne Thoresen, who was working on cerebral perfusion, was prompted to think about neuroprotection by stories of children who fell through the Norwegian ice and suffering prolonged drowning in iced water but emerged with preserved cerebral function. There were many potential therapies around which might achieve neural rescue, and most of these workers did not immediately move to hypothermia. Magnesium was an appealingly simple excitoxin receptor antagonist that protected cells in culture: the Reynolds group tested it in their piglet model without success Clemence M, Thornton JS, Penrice J, Amess P, Punwani S, Tyszczuk L et al. 31P MRS and quantitative diffusion and T2 MRI show no cerebroprotective effects of intravenous MgSO4 after severe transient hypoxia-ischaemia in the neonatal piglet. MAGMA 1996;4:114. . Gluckman and Gunn started by looking unsuccessfully at flunarizine, a calcium entry inhibitor Gunn AJ, Mydlar T, Bennet L, Faull RL, Gorter S, Cook C et al. The neuroprotective actions of a calcium channel antagonist, flunarizine, in the infant rat. Pediatr.Res. 1989;25:573-6 . Edwards picked on nitric oxide synthase inhibition which was also a failure Marks KA, Mallard C, Roberts I, Williams C, Gluckman P, Edwards AD. Nitric oxide synthase inhibition attenuates delayed vasodilation and increases injury following cerebral ischaemia in fetal sheep. Pediatr Res 1996;40:185-91. . Gluckman had success with his innovative studies of IGF-1, but could not immediately translate this to clinical practice Gluckman PD, Klempt N, Guan J, Mallard C, Sirimanne E, Dragunow M et al. A role for IGF-1 in the rescue of CNS neurons following hypoxic- ischemic injury. Biochem.Biophys.Res.Commun. 1992;182:593-9. . Experimental Neonatal Hypothermia Most neonatal researchers recognise work published in 1989 from Myron Ginsberg’s group as starting point of their interest in post-insult hypothermia. Ginsberg showed that a short period of hypothermia after hypoxia-ischaemia in adult rats produced significant protection in the hippocampus Busto R, Dietrich WD, Globus MY, Ginsberg MD. Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci.Lett 1989;101:299-304. . Soon Pusanelli’s group suggested that at least some of the strong neuroprotective effect of the canonical glutamate antagonist MK-801 was by reducing body temperature Buchan A,.Pulsinelli WA. Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J.Neurosci. 1990;10:311-6. . Before long there was a significant body of experimental work on post-ischaemic neuroprotection by hypothermia in mature animals Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 1989;20:904-10. Boris-Moller F, Smith M-L, Siesjö BK. Effects of hypothermia on ischemic brain damage: a comparison between preischemic and postischemic cooling. Neurosci.Res.Comm. 1989;5:87-94. Ikonomidou C, Mosinger JL, Olney JW. Hypothermia enhances protective effect of MK-801 against hypoxic/ischemic brain damage in infant rats. Brain Res 1989;487:184-7. Minamisawa H, Nordstrom CH, Smith ML, Siesjo BK. The influence of mild body and brain hypothermia on ischemic brain damage. J.Cereb.Blood Flow Metab 1990;10:365-74. Cardell M, Boris Moller F, Wieloch T. Hypothermia prevents the ischemia-induced translocation and inhibition of protein kinase C in the rat striatum. J Neurochem. 1991;57:1814-7. Chopp M, Chen H, Dereski MO, Garcia JH. Mild hypothermic intervention after graded ischemic stress in rats. Stroke 1991;22:37-43. Clifton GL, Jiang JY, Lyeth BG, Jenkins LW, Hamm RJ, Hayes RL. Marked protection by moderate hypothermia after experimental traumatic brain injury. J.Cereb.Blood Flow Metab. 1991;11:114-21. Coimbra C,.Wieloch T. Hypothermia ameliorates neuronal survival when induced 2 hours after ischaemia in the rat. Acta Physiol.Scand. 1992;146:543-4. Moyer DJ, Welsh FA, Zager EL. Spontaneous cerebral hypothermia diminishes focal infarction in rat brain. Stroke 1992;23:1812-6. Colbourne F,.Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res 1994;654:265-72. . These results also stimulated clinical scientists working with adults, who had apparent early success in clinical trials Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM et al. Treatment of traumatic brain injury with moderate hypothermia. N.Engl.J Med 1997;336:540-6. . The informal neonatal hypothermia interest group was developing: Gluckman visited London; Reynolds and Wyatt went to Oslo; Edwards went to Auckland; and Thoresen contacted Westin, then went to work in the Reynolds laboratory. Over the next year or so together and separately they produced a series of reports in piglets Thoresen M, Penrice J, Lorek A, Cady E, Wylezinska M, Kirkbride V et al. Mild Hypothermia following severe transient hypoxia-ischaemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 1995;37:667-70. Yue X, Mehmet H, Penrice J, Cooper C, Cady E, Wyatt JS et al. Apoptosis and necrosis in the newborn piglet brain following transient cerebral hypoxia-ischaemia. Neuropathol.Appl.Neurobiol. 1996;22:482-503. Haaland K, Loberg EM, Steen PA, Thoresen M. Posthypoxic hypothermia in newborn piglets. Pediatr Res 1997;41:505-12. Penrice J, Lorek A, Cady EB, Amess P, Wylezinska M, Cooper CE et al. Proton magnetic resonance spectroscopy of the brain during acute hypoxia-ischemia and delayed cerebral energy failure in the newborn piglet. Pediatr Res 1997;41:795-802. , immature rats Thoresen M, Bagenholm R, Loberg EM, Apricena F, Kjellmer I. Posthypoxic cooling of neonatal rats provides protection against brain injury. Arch.Dis.Child Fetal Neonatal Ed. 1996;74:F3-9. Sirimanne E, Blumberg RM, Bossano D, Gunning M, Edwards AD, Gluckman PD et al. The effect of prolonged modification of cerebral temperature on outcome following hypoxic-ischaemic brain injury in the infant rat. Pediatr Res 1996;39(4):591-7. Bona, E., Loberg, E., Bagenholm, R., Hagberg, H., and Thoresen, M. Protective effects of moderate hypothermia after hypoxia-ischaemia in a neonatal rat model: short and long-term outcome. Journal of Cerebral Blood Flow and Metabolism 17(Suppl 1), Abstract S857. 1997. and fetal sheep Gunn AJ, Gunn TR, De Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest. 1997;99:248-56. which showed repeatedly that post-insult hypothermia significantly reduced hypoxic-ischaemic brain damage in the developing brain. Trying to understand how and why cooling might work, they showed that it specifically reduced apoptosis Edwards AD, Yue X, Squier MV, Thoresen M, Cady EB, Penrice J et al. Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun 1995;217(3):1193-9. , and interrupted the excitiotoxic cascade Thoresen M, Satas S, Puka-Sundvall M, Whitelaw A, Hallestrom A, Loberg E et al. Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins. Neuroreport 1997;8:3359-62. . Thoresen recalls the immediacy of the first hypothermia experiment in the Reynolds laboratory. The room was full and she watched with Reynolds, Wyatt, Edwards and others as the biomarkers remained stubbornly normal after a very severe hypoxic insult which would normally have caused catastrophic secondary energy failure. In New Zealand there were similar experiences: Gunn says that he realised that hypothermia was going to work during his third experiment, as he watched the expected delayed injury fail to materialise. Early Clinical Studies As the experimental data continued to accumulate, clinical pilot studies were already being organised, although with some trepidation because of the prevailing view that cold was very dangerous for infants. There was some controversy over the relative benefits of selective head against whole body cooling. Tania and Alistair Gunn, first out of the clinical blocks, set out in Auckland to study local head cooling which they argued would have fewer side effects Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants following perinatal asphyxia; a safety study. Pediatrics 1998;102:885-992. ; Edwards and Azzopardi, now based at Hammersmith Hospital, delayed clinical studies until they had used a computer model to decide between the two Van Leeuwen GMJ, Hand JW, Lagendijk JJW, Azzopardi D, Edwards AD. Numerical modelling of temperature distributions within the neonatal head. Pediatr Res 2000;48:351-6. then started whole body cooling Azzopardi D, Robertson NJ, Cowan F, Rutherford M, Rampling M, Edwards AD. Pilot study of treatment with whole body hypothermia for neonatal encepalopathy. Pediatrics 2000;106:684-94. ; Thoresen and Andrew Whitelaw, relocated from Oslo to Bristol tried both methods Thoresen M,.Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy. Pediatrics 2000;106:92-9. . Cooling was now a topic of wider discussion in the neonatal community and other groups started to organise further experimental Laptook AR, Corbett RJ, Sterett R, Burns DK, Garcia D, Tollefsbol G. Modest hypothermia provides partial neuroprotection when used for immediate resuscitation after brain ischemia. Pediatr.Res. 1997;42:17-23. and further preliminary clinical studies Simbruner G, Haberl C, Harrison V, Linley L, Willeitner AE. Induced brain hypothermia in asphyxiated human newborn infants: a retrospective chart analysis of physiological and adverse effects. Intensive Care Med. 1999;25:1111-7. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr.Neurol. 2005;32:11-7. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr.Neurol. 2005;32:18-24. , (reviewed in Jacobs et al Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane.Database.Syst.Rev. 2007;CD003311. ). However, not everyone was convinced. The highly respected Vannucci laboratory had failed to find any protective effect of post-insult cooling Yager JY, Towfighi J, Vannucci RC. Influence of mild hypothermia on hypoxic ischaemic brain damage in the immature rat. Pediatr Res 1993;34:525-9. , and worse, Ginsberg’s group reported that hypothermic protection in mature rats was only temporary Dietrich WD, Busto R, Alonso O, Globus MY, Ginsberg MD. Intra-ischemic but not post-ischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J.Cereb.Blood Flow Metab 1993;13:541-9. . Many clinicians thought that the experiments models were over simplistic and unrepresentitive of the complex clinical situation. Others thought that brain damage might have occurred weeks or months earlier; although an MRI study from Hammersmith dispelled this myth Cowan F, Rutherford M, Groenendaal F, Eken P, Mercuri E, Bydder GM et al. Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet 2003;361:736-42. Randomised Controlled Trials The CoolCap study Nevertheless, cooling captured the imagination of one of the most influential figures in Neonatal Medicine. Jerry Lucey, the editor of the top-rated pediatric journal Pediatrics, had an extraordinary ability to spot new ideas, and he became a strong champion of cooling. He promoted hypothermia tirelessly, and in early 1997 made a critical introduction between Olympic Medical, a medium sized equipment company, and the cooling fraternity. In 1997, in his car on the way to Dulles International Airport after a series of meetings largely organised by Lucey, Jay Jones the owner of Olympic Medical decided to fund a randomised controlled trial of hypothermic neural rescue therapy in newborn infants. Olympic would construct a head cooling device, the Olympic Cool-Cap System, and provide practical and financial support for the trial. Gluckman and Wyatt would be principal investigators and the scientific committee which developed and ran the trial joined hypothermia researchers like Edwards and Whitelaw, with new experts Donna Ferriero, Richard Polin, Roberta Ballard and Charlene Robertson. The newcomers were not all convinced baby-coolers; Ferriero, also a distinguished neuroprotection experimentalist, was particularly sceptical; but they brought a range of new skills essential to taking hypothermia into a major randomised trial. Arguably the most important roles in delivering the trial were taken by Ted Weiler, an indefatigable engineer from Olympic Medical, and Gunn who became the Scientific Officer. The CoolCap study studied cooling for 72 hours started within 6 hours of delivery. The protocol was based on the Auckland pilot studies, but was somewhat arbitrary; the relative merits of different temperatures or lengths of cooling were unclear, and the researchers used best estimates based on their animal experiments, cautiously choosing the upper band of the expected therapeutic range. No-one knew with certainty what effect size to predicit or even what the best primary outcome was. On the divisive question of selective head versus whole body cooling, in the almost total absence of useful data they compromised and used rectal temperature to control a head cooling device. CoolCap thus studied the effect of cooling the whole baby to 34.5oC with the expectation (some said hope) that the brain might be a degree or so cooler. The first infant was enrolled at Columbia Presbyterian Medical Center, New York, on July 1, 1999 and all data were collected, audited, and prepared for analysis by fall 2003. The result was reported at Lucey's annual Washington DC 'Hot Topics in Neonatology' meeting in December 2003 with full publication in The Lancet in 2005. CoolCap showed a non-significant trend to improvement with cooling in the primary outcome of death or disability at 18 months overall, but a clear and significant benefit when infants with very severe or long established brain injury were excluded Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005;365:663-70. Gunn A, Gluckman PD, Wyatt JS, Thoresen M, Edwards AD. Selective head cooling after neonatal encephalopathy. Lancet 2005;365:1619-20. . This was not quite the definitive result they hoped for, but the researchers remained resolute; Gluckman confided to Edwards as they relaxed together after the data presentation in Washington, that he thought they would never do more important work. The National Institute of Child Health and Human Development Study After the CoolCap trial another major study was published by the National Institute for Child Health and Human Development (NICHD) Neonatal Research Network. The CoolCap researchers had previously had lengthy discussions with the network about collaboration because although the network had no experience of hypothermia they had a strong track record of patient recruitment. However after detailed discussions around the final CoolCap protocol broke down, the Network began a separate trial led by Seetha Shankaran. Some network members were setting up animal models of hypothermic neural rescue, providing valuable experience for preliminary experiments Shankaran S, Laptook A, Wright LL, Ehrenkranz RA, Donovan EF, Fanaroff AA et al. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics 2002;110:377-85. . The NICHD trial found a significant effect of cooling, although the study was criticised in some quarters for temperature instability in the control group Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N.Engl.J Med. 2005;353:1574-84. . The TOBY Trial The question which now faced the community was: should cooling become standard of care? Opinions were divided. Some observers thought the evidence was sufficient, particularly if the growing number of pilot or smaller studies were considered Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane.Database.Syst.Rev. 2007;CD003311. and in December 2006 the Federal Drugs Administration (FDA) approved the Olympic Cool-Cap System for clinical use. However others pointed out that the results were at best statistically marginal and urged scepticism Kirpalani H, Barks J, Thorlund K, Guyatt G. Cooling for neonatal hypoxic ischemic encephalopathy: do we have the answer? Pediatrics 2007;120:1126-30. . Worryingly, hypothermia trials for head trauma in adults and older children were failing to show benefit Hutchison JS, Ward RE, Lacroix J, Hebert PC, Barnes MA, Bohn DJ et al. Hypothermia therapy after traumatic brain injury in children. N.Engl.J.Med. 2008;358:2447-56. Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, Smith KR, Jr. et al. Lack of effect of induction of hypothermia after acute brain injury. N.Engl.J.Med. 2001;344:556-63. . A review meeting organised by NICHD advised that cooling was an emerging therapy but not standard of care; the community awaited more data Higgins RD, Raju TN, Perlman J, Azzopardi DV, Blackmon LR, Clark RH et al. Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop. J.Pediatr. 2006;148:170-5. . After a couple of years during which even the original researchers found it difficult always to agree, the last major trial that had grown out of the original experimentalist group was completed. The TOtal BodY hypothermia for pernatal asphyxia trial (TOBY), led by Azzopardi backed by distinguished trials specialist Peter Brocklehurst and the UK National Perinatal Epidemiology Unit, developed from the Hammersmith pilot study of whole body cooling, but collected the data needed to allow meta-analysis with both CoolCap and the NICHD studies. TOBY had the 'advantage' of being delayed in starting by the funding timetable of the Medical Research Council (UK), so that it was still in progress when CoolCap and the NICHD trial reported marginal benefits, making it clear that the trial size should be increased. When TOBY reported it was considerably larger than either previous study and yet showed remarkable consistency with both those trials; the point estimate for effect was similar and meta-analysis (detailed below) showed unequivocally that cooling increases an infants chance of surviving without neurological deficits at 18 months and reduces neurodevelopmental impairment in survival Azzopardi DV, Strohm B, Edwards AD et al Moderate hypothermia to treat perinatal asphyxial encephalopathy N Engl J Med 2009;361:1349-58 . The memories of some of the researchers involved in bringing hypothermic neural rescue into clinical practice have recently been collatedEdwards AD The Discovery of Hypothermic Neural Rescue Therapy for Perinatal Hypoxic-Ischemic Encephalopathy Seminars in Pediatric Neurology Volume 16, Issue 4, December 2009, Pages 200-206 . = Mechanisms of Hypothermic Neuroprotection after Birth Asphyxia = Much of what is known about the mechanisms of hypothermic neuroprotection is gathered from studies in mature and adult models. What follows uses some of these data while trying to focus on the immature brain. More information, particularly on adults, is given in the article Therapeutic hypothermia. Hypoxia-ischaemia Cerebral hypoxia-ischaemia results in reduced cerebral oxidative metabolism, cerebral lactic acidosis and cell membrane ionic transport failure; if prolonged there is necrotic cell death. Siesjo BK, Katsura K, Kristian T. The biochemical basis of cerebral ischemic damage. J Neurosurg.Anesthesiol. 1995;7:47-52.Siesjo BK. Cell damage in the brain: a speculative synthesis. Acta Psychiatr.Scand.Suppl 1984;313:57-91. Although rapid recovery of cerebral energy metabolism occurs following successful resuscitation this is followed some hours later by a secondary fall in cerebral high energy phosphates accompanied by a rise in intracellular pH, and the characteristic cerebral biochemical disturbance at this stage is a lactic alkalosisTaylor DL, Edwards AD, Mehmet H. Oxidative metabolism, apoptosis and perinatal brain injury. Brain Pathol. 1999;9:93-117.. In neonates, the severity of this secondary impairment in cerebral metabolism are associated with abnormal subsequent neurodevelopmental outcome and reduced head growthRoth SC, Edwards AD, Cady EB, Delpy DT, Wyatt JS, Azzopardi D et al. Relation between cerebral oxidative metabolism following birth asphyxia, and neurodevelopmental outcome and brain growth at one year. Dev.Med.Child Neurol. 1992;34:285-95.Robertson NJ, Cox IJ, Cowan FM, Counsell SJ, Azzopardi D, Edwards AD. Cerebral intracellular lactic alkalosis persisting months after neonatal encephalopathy measured by magnetic resonance spectroscopy. Pediatr.Res. 1999;46:287-96.. Several adverse biological events contribute to this secondary deterioration, including: release of excitatory amino acids which activate N-methyl-D-aspartate (NMDA) and amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors on neurons (30,37) and oligodendroglial precursors, accumulation of excitatory neurotransmitters, generation of reactive oxygen radicals, intracellular calcium accumulation and mitochondrial dysfunctionSiesjo BK, Elmer E, Janelidze S, Keep M, Kristian T, Ouyang YB et al. Role and mechanisms of secondary mitochondrial failure. Acta Neurochir.Suppl (Wien.) 1999;73:7-13.. Whilst necrotic cell death is prominent in the immediate and acute phases of severe cerebral insults, the predominant mode of death during the delayed phase of injury appears to be apoptosisNorthington FJ, Ferriero DM, Graham EM, Traystman RJ, Martin LJ. Early Neurodegeneration after Hypoxia-Ischemia in Neonatal Rat Is Necrosis while Delayed Neuronal Death Is Apoptosis. Neurobiol.Dis. 2001;8:207-19.. Neuroprotective mechanisms need to interact with these mechanisms to have beneficial effect. Newborn hypoxic-ischaemic brain injury differs from injury in the adult brain in several ways: NMDA receptor toxicity is much higher in the immature brainMcDonald & Johnston Brain Res Rev.15:41,1990 . Apoptotic mechanisms including activation of caspases, translocation of apoptosis-inducing factor and cytochrome-c release are much greater in the immature than the adultWang X et al. J Neurosci 29:2588,2009 Northington et al. J Neurosci. 21:1931,2001 Gill R et al. J Cereb Blood Flow Metab 22:420,2002 . The inflammatory activation is different with less contribution from polymorphonuclear cellsBona et al. Ped Res 45:500,1999 and a more prominent role of IL-18Hedtjarn M et al. J Neurosci 22:5910,2002 whereas IL-1, which is critical in the adult brainBoutin et al. J Neurosci. 21:5528, 2001 , is less importantHedtjarn et al. Dev Neurosci 27:143,2005 . The anti-oxidant system is underdeveloped with reduced capacity to inactivate hydrogen peroxideFerriero DM N Engl J Med 351:1985,2004 . Actions of Hypothermia Mild hypothermia helps prevent disruptions to cerebral metabolism both during and following cerebral insults. Hypothermia decreases the cerebral metabolic rate for glucose and oxygen and reduces the loss of high energy phosphates during hypoxia-ischaemiaErecinska M, Thoresen M, Silver IA. Effects of hypothermia on energy metabolism in mammalian central nervous system. J Cereb.Blood Flow Metab 2003;23:513-30. and during secondary cerebral energy failureLorek A, Takei Y, Cady EB, Wyatt JS, Penrice J, Edwards AD et al. Delayed ('secondary') cerebral energy failure following acute hypoxia-ischaemia in the newborn piglet: continuous 48-hour studies by 31P magnetic resonance spectroscopy. Pediatr Res 1994;36:699-706. , and reduces delayed cerebral lactic alkalosis Amess PN, Penrice J, Cady EB, Lorek A, Wylezinska M, Cooper CE et al. Mild hypothermia after severe transient hypoxia-ischemia reduces the delayed rise in cerebral lactate in the newborn piglet. Pediatr.Res. 1997;41:803-8..23;24 The simultaneous increase in cytotoxic oedema and loss of cerebral cortical activity that accompanies secondary energy failure is also preventedGunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics 1998;102:1098-106.. Hypothermia appears to have multiple effects at a cellular level following cerebral injury. Hypothermia reduces vasogenic oedema, haemorrhage and neutrophil infiltration after traumaSmith SL,.Hall ED. Mild pre- and posttraumatic hypothermia attenuates blood-brain barrier damage following controlled cortical impact injury in the rat. J Neurotrauma 1996;13:1-9.. The release of excitatory neurotransmitters is reduced, limiting intracellular calcium accumulationBusto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 1989;20:904-10. Nakashima K,.Todd MM. Effects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization. Stroke 1996;27:913-8.Thoresen M, Satas S, Puka-Sundvall M, Whitelaw A, Hallestrom A, Loberg E et al. Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins. Neuroreport 1997;8:3359-62.. Free radical production is lessened, which protects cells and cellular organelles from oxidative damage during reperfusionGlobus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem. 1995;65:1704-11.. In addition mild hypothermia may reduce the activation of the cytokine and coagulation cascades through increased activation of suppressor signalling pathways, and by inhibiting release of platelet activating factorAkisu M, Huseyinov A, Yalaz M, Cetin H, Kultursay N. Selective head cooling with hypothermia suppresses the generation of platelet-activating factor in cerebrospinal fluid of newborn infants with perinatal asphyxia. Prostaglandins Leukot.Essent.Fatty Acids 2003;69:45-50.. Many of the effects induced by mild hypothermia may help to reduce the number of cells undergoing apoptosis. Experimental and clinical studies indicate that the number of apoptotic neurons is reduced caspase activity is lessened and cytochrome c translocation is diminished by mild hypothermia Edwards AD, Yue X, Squier MV, Thoresen M, Cady EB, Penrice J et al. Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem.Biophys.Res.Commun. 1995;217:1193-9.Xu L, Yenari MA, Steinberg GK, Giffard RG. Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. J Cereb.Blood Flow Metab 2002;22:21-8., and there may be an increase in expression of the anti-apoptotic protein BCl-2Zhang Z, Sobel RA, Cheng D, Steinberg GK, Yenari MA. Mild hypothermia increases Bcl-2 protein expression following global cerebral ischemia. Brain Res.Mol.Brain Res. 2001;95:75-85.. =Effect of Therapeutic Hypothermia in Clincial Trials= Meta-analysis of trials data A number of randomised controlled trials have now been carried out. Early synthesis of the available data by the Cochrane Collaboration suggested that there was a beneficial effect but did not provide unequivocal support for general application ^ Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane.Database.Syst.Rev. 2007;CD003311. However a meta-analysis of all studies published in late 2009 included new data, in particular the TOBY trial, and this provided conclusive evidence that cooling reduces the adverse effects of birth asphyxiaEdwards AD, Brocklehurst P, Halliday H, Gunn A, Juszczak E, Levine M Strohm B, Thoresen M, Whitelaw A, Azzopardi DV Neurological outcome at 18 months of age following moderate hypothermia in newborn infants with hypoxic ischaemic encephalopathy Brit Med Journal 2009 in press. This analysis found 3 trials, the CoolCap, NICHD and TOBY trials which measured neurological outcome at least 18 months after birth. These trials report a total of 767 infants. Taken together they showed a significant benefit of cooling with a significant reduction in death or disability at 18 months after birth: typical Risk Ratio, 0.81 (95% Confidence Intervals, 0.71, 0.93), P=0.002. Treatment with hypothermia was consistently associated with an increased rate of normal survival survival: typical Risk Ratio, 1.53 (95% Confidence Intervals, 1.22, 1.93), P <0.001. There was a significant reduction in cerebral palsy amongst infants treated with hypothermia compared with controls. The relative effects of selective head and whole body cooling seem indistinguishable. 11 trials reported mortality rates after cooling. Meta-analysis of these data showed that fewer infants treated with prolonged moderate hypothermia died: typical Risk Ratio 0.78 (95% Confidence Interval, 0.66, 0.93) P=0.004. Current state of the evidence While most observers currently regard hypothermic neural rescue therapy as an evidence-based clinical treatment which increases any individual child's chance of surviving without brain damage detectable at 18 months by about 50%, there remains much that is unknown. Long-term follow-up is in progress to ensure that the benefits persist, although an imaging study nested in TOBY also found reduced brain tissue damage in cooled infants which is encouraging Rutherford MA, Ramenghi LA, Edwards AD, Brocklehurst P, Halliday H, Levene M, Strohm B, Thoresen M, Whitelaw A, Azzopardi D. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurology Nov 5 2009 PMID: 19896902 It is not clear if cooling initiated later will be beneficial, and the NICHD network has set out to investigate this. The ICE trial, a pragmatic study which emphasises the role of transport, is awaited. Trials are beginning of therapies added to cooling, such as Xenon gas or erythropoietin. The simplicity which attracted empyricists to cooling centuries ago now makes hypothermic neural rescue a potentially transforming therapy for low-resource environments where birth asphyxia remains a major cause of death and disability. Ironically this brings back the problem of cooling infants in an environment where modern resuscitation and intensive care are not available Robertson NJ, Nakakeeto M, Hagmann C, Cowan FM, Acolet D, Iwata O et al. Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial. Lancet 2008;372:801-3. . See also *Birth Trauma Association *Birth anoxia *Fetal distress *Obstetrical complications *Postsurgical complications *Pre- and perinatal psychology *Pregnancy *Premature birth *Postmature birth = References =